The prevalence of obesity and asthma has significantly increased over the past two decades. Epidemiologic studies show a positive association between obesity and ainway hyperresponsiveness (AHR), one of the defining features of asthma pathophysiology. Although both the inflammatory and mechanical effects of obesity on the airways have been implicated as possible mechanisms, the majority of studies to date have focused on the inflammatory-mediated effects of obesity. However, given the observed lack of association between obesity and inflammatory markers known to be associated with asthma, other mechanisms must be considered, including the mechanical effects of obesity on AHR. Thus our overall aim is to determine the mechanical effects of obesity on ainway caliber, ainway smooth muscle (ASM) tone and deep inspiration (DI) response, features previously shown to be involved in AHR. We hypothesize that the mechanical effects of obesity cause AHR by decreasing forces on the airways leading to airway narrowing and increased ASM tone and impairment in DI response. We propose to study four groups (15 obese asthmatics, 15 non-obese asthmatics, 15 obese non-asthmatics, and 15 controls) closely matched by age, sex, race and height using high resolution CT. In addition, we will assess ASM response to DI using a modified methacholine challenge to study the effects of obesity on bronchoprotection and bronchoconstriction in obesity controlling for asthma status. Receipt of this 3-year award will enhance my career development as a clinical investigator by 1) providing me with supported time to pursue didactic training relevant to this proposal, 2) expanding my technical skills through implementation of the proposed research plan and by having direct hands-on experience with participants, 3) providing me the time and support necessary to transition into an independent investigator. RELEVANCE (See instructions): The proposed project will 1) address important gaps in our knowledge regarding the mechanisms by which the mechanical effects of obesity contribute to AHR;2) identify new potential non-pharmaceutical target(s) for the management of asthma in this high risk population;3) serve as a platform to gain the experience and skills necessary to achieve my ultimate goal of becoming an independent clinical investigator in pulmonary physiology. (End of Abstract)